Anaphylaxis mortality in the perioperative setting: Epidemiology, elicitors, risk factors and knowledge gaps.

Perioperative anaphylaxis (PA) is a severe condition that can be fatal, but data on PA mortality are scarce. The aim of this article is to review the epidemiology, elicitors and risk factors for PA mortality and identify knowledge gaps and areas for improvement regarding the management of severe PA. PA affects about 100 cases per million procedures. Mortality is rare, estimated at 3 to 5 cases per million procedures, but the PA mortality rate is higher than for other anaphylaxis aetiologies, at 1.4% to 4.8%. However, the data are incomplete. Published data mention neuromuscular blocking agents and antibiotics, mainly penicillin and cefazolin, as the main causes of fatal PA. Reported risk factors for fatal PA vary in different countries. Most frequently occurring comorbidities are obesity, male gender, cardiovascular diseases and ongoing treatment with beta-blockers. However, there are no clues about how these factors interact and the impact of individual risk factors. The pathophysiology of fatal PA is still not completely known. Genetic factors such as deficiency in PAF-acetyl hydrolase and hereditary alpha-tryptasemia, have been reported as modulators of severe anaphylaxis and possible targets for specific treatments. Our review underlines unmet needs in the field of fatal PA. Although we confirmed the need for timely administration of an adequate dose of adrenaline and the proper infusion of fluids, there is no evidence-based data on the proper dose of intravenous titrated adrenaline and which clinical manifestations would flag the need for fluid therapy. There are no large clinical studies supporting the administration of alternative vasopressors, such as glucagon and methylene blue. Further research on pathophysiological mechanisms of PA and its severity may address these issues and help clinicians to define new therapeutic approaches.

Management of Refractory Anaphylaxis: An Overview of Current Guidelines.

In this review, we compare different refractory anaphylaxis (RA) management guidelines focusing on cardiovascular involvement and best practice recommendations, discuss postulated pathogenic mechanisms underlining RA and highlight knowledge gaps and research priorities. There is a paucity of data supporting existing management guidelines. Therapeutic recommendations include the need for the timely administration of appropriate doses of aggressive fluid resuscitation and intravenous (IV) adrenaline in RA. The preferred second-line vasopressor (noradrenaline, vasopressin, metaraminol and dopamine) is unknown. Most guidelines recommend IV glucagon for patients on beta-blockers, despite a lack of evidence. The use of methylene blue or extracorporeal life support (ECLS) is also suggested as rescue therapy. Despite recent advances in understanding the pathogenesis of anaphylaxis, the factors that lead to a lack of response to the initial adrenaline and thus RA are unclear. Genetic factors, such as deficiency in platelet activating factor-acetyl hydrolase or hereditary alpha-tryptasaemia, mastocytosis may modulate reaction severity or response to treatment. Further research into the underlying pathophysiology of RA may help define potential new therapeutic approaches and reduce the morbidity and mortality of anaphylaxis.

Fatal and near-fatal anaphylaxis: The Allergy-Vigilance® Network data (2002-2020).

BACKGROUND: Having a better understanding of the risk factors of severe anaphylaxis is a crucial challenge for physicians. METHODS: To retrospectively analyse fatal/near-fatal anaphylaxis cases recorded by the Allergy-Vigilance® Network (2002-2020) and evaluate the characteristics associated with survival, age and allergens. RESULTS: Among the 3510 anaphylaxis cases documented in the network, 70 (2%) patients (males: 57%; mean age: 35.4 y) presented grade 4 (Ring-Messmer) anaphylaxis and 25 died (19 food-related); 33% had a history of asthma. The main allergens were food (60%; peanut, 20%; milks, 11%) involved in 25/26 cases in children and in 17/44 (39%) cases in adults. Non-food anaphylaxis was related to drugs/latex (24%; neuromuscular blocking agents, 10%; betalactamins, 6%), Hymenoptera (16%). Three food-related cases (one death) occurred during oral food challenge in children. Patients with a food allergy were younger (22.2 years vs. 55 years, p < .001), had more likely a history of asthma (50% vs. 7%; p < .001), a pre-existing allergy (62% vs. 18%; p < .001) compared with other allergies. A cofactor was identified in 35 cases (50%) but predominantly in adults as opposed to children (64% vs. 27%; p = .01). The patients who died were younger (25.6 vs. 40.8 years; p = .01) than the survivors and mostly presented bronchospasm (56% vs. 29%; p = .05). Gaps in the prevention and management of anaphylaxis were noted in 15 cases (21%). CONCLUSIONS: Severe food anaphylaxis has specific features compared with other causes such as young age, asthma history and exercise. Food is also involved in severe anaphylaxis in adults that should not be underestimated.

Determining clinical predictors to identify non-specific abdominal pain and the added value of laboratory examinations: A prospective derivation study in a paediatric emergency department.

AIM: To develop a model to discriminate non-specific abdominal pain (NSAP) from organic pain in the paediatric emergency department (PED) and evaluate the added value of laboratory markers. METHODS: Prospective cohort study in an urban French PED including all patients aged ≥4 years with abdominal pain between November 2020 and May 2021. The outcome was the discrimination between NSAP (patients coded to have only "pain" or "constipation") and organic pain (all other diagnoses) using stepwise backward multivariate logistic regression method with bootstrap resampling. RESULTS: The study enrolled 246 patients. Overall, 163 patients (66.2%) had NSAP. Four variables associated with organic pain: pain in the epigastric region (OR 0.48 [0.23-0.99]), worsening pain (0.57 [0.32-0.99]), pain migration (0.42 [0.17-0.99]) and vomiting (0.47 [0.26-0.84]) were integrated in a clinical model. To discriminate NSAP with a probability of 65%, model sensitivity was 71.8% (64.9-78.7), specificity was 53.0% (42.3-63.7), and the Net Benefit (NB) was 15.4%. White Blood Count and C-reactive protein results improved discriminative capacity of the model (AUC 0.708 [0.643-0.773] vs. 0.654 [0.585-0.723], p = 0.01) with a supplementary NB of 12%. Patient follow-up showed 95% diagnostic accuracy. CONCLUSION: This study reveals a four-clinical predictor model with a NB of 15% in predicting NSAP. Validation studies are necessary.

The global burden of illness of peanut allergy: A comprehensive literature review.

Peanut allergy (PA) currently affects approximately 2% of the general population of Western nations and may be increasing in prevalence. Patients with PA and their families/caregivers bear a considerable burden of self-management to avoid accidental peanut exposure and to administer emergency medication (adrenaline) if needed. Compared with other food allergies, PA is associated with higher rates of accidental exposure, severe reactions and potentially fatal anaphylaxis. Approximately 7%-14% of patients with PA experience accidental peanut exposure annually, and one-third to one-half may experience anaphylaxis, although fatalities are rare. These risks impose considerably high healthcare utilization and economic costs for patients with PA and restrictions on daily activities. Measures to accommodate patients with PA are often inadequate, with inconsistent standards for food labelling and inadequate safety policies in public establishments such as restaurants and schools. Children with PA are often bullied, resulting in sadness, humiliation and anxiety. These factors cumulatively contribute to significantly reduced health-related quality of life for patients with PA and families/caregivers. Such factors also provide essential context for risk/benefit assessments of new PA therapies. This narrative review comprehensively assessed the various factors comprising the burden of PA.

Food-induced anaphylaxis in infancy compared to preschool age: A retrospective analysis.

OBJECTIVE: Little is known regarding food anaphylaxis in infancy. We aimed to describe specificities of food anaphylaxis in infants (≤12 months) as compared to preschool children (1-6 years). METHODS: We conducted a retrospective study of all food anaphylaxis cases recorded by the Allergy Vigilance Network from 2002 to 2018, in preschool children focusing on infants. RESULTS: Of 1951 food anaphylaxis reactions, 61 (3%) occurred in infants and 386 (20%) in preschool children. Two infants had two anaphylaxis reactions; thus, we analyzed data among 59 infants (male: 51%; mean age: 6 months [SD: 2.9]); 31% had a history of atopic dermatitis, 11% of previous food allergy. The main food allergens were cow's milk (59%), hen's egg (20%), wheat (7%) and peanut (3%) in infants as compared with peanut (27%) and cashew (23%) in preschool children. Anaphylaxis occurred in 28/61 (46%) cases at the first cow's milk intake after breastfeeding discontinuation. Clinical manifestations were mainly mucocutaneous (79%), gastrointestinal (49%), respiratory (48%) and cardiovascular (21%); 25% of infants received adrenaline. Hives, hypotension and neurologic symptoms were more likely to be reported in infants than in preschool children (P = .02; P = .004; P = .002, respectively). Antihistamines and corticosteroids were more often prescribed in preschool children than in infants (P = .005; P = .025, respectively). CONCLUSION: Our study found that in infants presenting with their first food allergy, in a setting with a high rate of infant formula use, the most predominant trigger was cow's milk. As compared to older preschool children, hives, hypotonia and hypotension were more likely to be reported in infants. We believe that this represents a distinct food anaphylaxis phenotype that can further support developing the clinical anaphylaxis criteria in infants.

Severe preschool asthmatics have altered cytokine and anti-viral responses during exacerbation.

BACKGROUND: Preschool asthma/recurrent wheeze is a heterogeneous condition. Different clinical phenotypes have been described, including episodic viral wheeze (EVW), severe intermittent wheeze (SIW), and multiple-trigger wheeze (MTW). OBJECTIVE: To compare clinical, viral, and inflammatory/immune profiling at exacerbation between MTW, SIW, and EVW phenotypes. METHODS: Multicenter, prospective, observational cohort (VIRASTHMA-2). Children (1-5 years) with preschool asthma were enrolled during hospitalization for a severe exacerbation. History and anamnestic data, plasma, and nasal samples were collected at exacerbation (T1) and at steady state, 8 weeks later (T2), and sputum samples were collected at T1. RESULTS: A total of 147 children were enrolled, 37 (25%) had SIW, 18 (12.2%) EVW, and 92 (63%) MTW. They were atopic (47%), exposed to mold (22%) and cigarette smoke (50%), and prone to exacerbations (≥2 in the previous year in 70%). At exacerbation, at least one virus was isolated in 94% and rhinovirus in 75%, with no difference between phenotypes. Children with MTW and SIW phenotypes displayed lower plasma concentrations of IFN-γ (P = .002), IL-5 (P = .020), TNF-α (P = .038), IL-10 (P = .002), IFN-ß (P = .036), and CXCL10 (P = .006) and lower levels of IFN-γ (P = .047) in sputum at exacerbation than children with EVW. At T2, they also displayed lower plasma levels of IFN-γ (P = .045) and CXCL10 (P = .013). CONCLUSION: Among preschool asthmatic children, MTW and SIW, prone to exacerbations, display lower systemic levels of Th1, Th2 cytokines, pro- and anti-inflammatory cytokines, and antiviral responses during severe virus-induced exacerbation.

Anaphylaxis admissions in pediatric intensive care units: Follow-up and risk of recurrence.

BACKGROUND: Data about the risk of anaphylaxis recurrence in children are lacking. We assessed anaphylaxis recurrence and medical follow-up in a cohort of children previously hospitalized in a French pediatric intensive care unit (PICU) for anaphylaxis. METHODS: We conducted a telephone survey of 166 children (≤18 years) hospitalized from 2003 to 2013. RESULTS: In all, 106 (64%) completed the survey (boys, 59%; mean age [SD]: 15.3 years [5.5]). The main index triggers were drugs (45%) and foods (37%). The mean duration follow-up was of 7.7 years (SD: 2.4). Thirty-eight (36%) children experienced 399 new allergic reactions during a follow-up period of 282 patient-years (incidence rate: 1.4/100 patients/y; 95% CI: 0.64-2.04). Twelve children experienced 19 anaphylaxis reactions including five requiring PICU admission (anaphylaxis recurrence rate: 0.20/100 patients/y; 95% CI non-calculable). Food was the trigger for 79% of recurrent reactions and drugs for 8%. The food trigger was previously known in 83%, the same as the index trigger in 69%. Overall, 1.5% of the recurrent reactions were treated with adrenaline injection and 8% an emergency hospital admission. Patients with recurrence had more likely a history of food allergy (P < 10-4 ), asthma (P < 0.005), atopic dermatitis (P < 0.05) than those without. 31% of the 50 children with food allergy did not see an allergist, 23% had no adrenaline auto-injector, and 26% lacked a school individual healthcare plan. CONCLUSIONS: Following a PICU admission for anaphylaxis, recurrence is high in children with food allergy compared with drug allergy. Allergic comorbidities increase the risk. Medical follow-up has to be improved for these at-risk children.

Food-induced fatal anaphylaxis: From epidemiological data to general prevention strategies.

BACKGROUND: Anaphylaxis hospitalizations are increasing in many countries, in particular for medication and food triggers in young children. Food-related anaphylaxis remains an uncommon cause of death, but a significant proportion of these are preventable. AIM: To review published epidemiological data relating to food-induced anaphylaxis and potential risk factors of fatal and/or near-fatal anaphylaxis cases, in order to provide strategies to reduce the risk of severe adverse outcomes in food anaphylaxis. METHODS: We identified 32 published studies available in MEDLINE (1966-2017), EMBASE (1980-2017), CINAHL (1982-2017), using known terms and synonyms suggested by librarians and allergy specialists. RESULTS: Young adults with a history of asthma, previously known food allergy particularly to peanut/tree nuts are at higher risk of fatal anaphylaxis reactions. In some countries, cow's milk and seafood/fish are also becoming common triggers of fatal reactions. Delayed adrenaline injection is associated with fatal outcomes, but timely adrenaline alone may be insufficient. There is still a lack of evidence regarding the real impact of these risk factors and co-factors (medications and/or alcohol consumption, physical activities, and mast cell disorders). CONCLUSIONS: General strategies should include optimization of the classification and coding for anaphylaxis (new ICD 11 anaphylaxis codes), dissemination of international recommendations on the treatment of anaphylaxis, improvement of the prevention in food and catering areas, and dissemination of specific policies for allergic children in schools. Implementation of these strategies will involve national and international support for ongoing local efforts in relationship with networks of centres of excellence to provide personalized management (which might include immunotherapy) for the most at-risk patients.

[Food allergy in children and management in the school setting: what are the adequate precautions?] / Allergie alimentaire de l'enfant et accueil en milieu scolaire : quelles précautions ?

Food allergy prevalence is increasing particularly in young children. A correct diagnosis requires accurate evaluation by an allergist to determine the food trigger(s), the food(s) that require(s) to be avoided, the potential need for an emergency kit (with/without an adrenaline auto-injector) and for an individual healthcare plan at school. This ma-nuscript aims at describing the precautions required to take care of food allergic children, particularly the indica-tions for adrenaline auto-injectors and individual healthcare plans at school. Individual healthcare plan actually used in France should be clarified with the implementation of a unique emergency action plan to improve the acceptance of food-allergic children in a school setting.

Les allergies alimentaires sont de plus en plus fréquentes chez l'enfant et leur diagnostic repose sur une évaluation allergologique rigoureuse pour préciser le ou les allergènes, le régime d'éviction mais aussi les aliments autorisés, l'intérêt ou non d'une trousse d'urgence (avec ou sans auto-injecteur d'adrénaline) et d'un projet d'accueil indi-vidualisé pour encadrer la scolarité. Cet article synthétise les précautions nécessaires à la prise en charge d'un enfant ayant une allergie alimentaire, notamment les conditions de prescription d'une trousse d'urgence avec adrénaline et les indications de mise en place d'un projet d'accueil individualisé pour allergie alimentaire. Ce projet d'accueil va évoluer prochainement vers une simplification et une harmonisation afin d'améliorer encore l'accueil des enfants allergiques en milieu scolaire.

Virus-triggered exacerbation in allergic asthmatic children: neutrophilic airway inflammation and alteration of virus sensors characterize a subgroup of patients.

BACKGROUND: Viruses are important triggers of asthma exacerbations. They are also detected outside of exacerbation. Alteration of anti-viral response in asthmatic patients has been shown although the mechanisms responsible for this defect remain unclear. The objective of this study was to compare in virus-infected and not-infected allergic asthmatic children, aged 6 to 16 years, admitted to hospital for a severe exacerbation, the innate immune response and especially the expression of pattern recognition receptor (PRR) and their function. METHODS: Virus identification was performed both during the exacerbation and at steady state (eight weeks later). Data assessed at both periods included clinical features, anti-viral response and inflammation (in sputum and plasma), and PRR expression/function in blood mononuclear cells. RESULTS: Viruses were identified in 46 out of 72 children (median age 8.9 years) during exacerbation, and among them, in 17 at steady state. IFN-ß, IFN-γ and IL-29 levels in sputum and plasma were similar between infected and not infected patients at both times, as well as the expression of TLR3, RIG-I and MDA5 in blood monocytes and dendritic cells. Airway inflammation in infected patients was characterized by significantly higher IL-5 concentration and eosinophil count. Compared to patients only infected at exacerbation, the re-infected children significantly exhibited lower levels of IFN-γ in plasma and sputum at exacerbation associated with modifications in PRR expression and function in blood mononuclear cells. These re-infected patients also presented an airway neutrophilic inflammation at steady state. CONCLUSION: Our results reports in asthmatic children that impaired anti-viral response during virus-induced exacerbation is more pronounced in a subgroup of patients prone to re-infection by virus. This subgroup is characterized by altered PRR function and a different pattern of airway inflammation. TRIAL REGISTRATION: This multicenter prospective study was approved by the regional investigational review board (ref: 08/07).

Individual healthcare plan for allergic children at school: Lessons from a 2015-2016 school year survey.

BACKGROUND: The individual healthcare plan (IHP) was implemented in schools in France in 2003 to improve management of allergic children. Our objectives were to assess the practical aspects of IHP (excluding asthma) and allergic reactions occurring at school. METHODS: Prospective study conducted in the North Department (France) during the 2015/2016 school year. Two questionnaires were developed: one for the school doctors (n = 67) and one for the school principals (n = 2372). RESULTS: Data from 336 (25%) of the 1325 IHPs (0.24% of children) were collected (mean age: 8 years; food allergy [FA]: 94% [peanut = 44%, nuts = 54%], venom: 4%). Wide variations in emergency kit (EK) medications were observed: antihistamines (84%), oral corticosteroids (79%), adrenaline auto-injectors (70%), and inhaled bronchodilators (65%). Six hundred and seventy (28%) school principals' responses, representing 81% of all IHPs, were analyzed. A total of 1935 EKs were stored (mean: 2.8/school), one or more with adrenaline, by 213 (32%) schools: in the class room (33%), the nursery (14%), or the principal's office (10%). Sixty, mainly, mild-to-moderate allergic reactions (adrenaline injection: 2) occurred in 44 schools (0.09/school/year), in children with previously undocumented allergy in 50%. FA was highly suspected in 92%. CONCLUSION: Individual healthcare plan is mainly implemented for FA. Anaphylaxis remains rare in the school setting, and FA is often a suspected cause of reaction. Staff training should be improved. Application of the recommendations regarding the content and accessibility of EK and a widespread emergency action plan is needed.

Utility of measuring FEV0.75/FVC ratio in preschoolers with uncontrolled wheezing disorder.

Uncontrolled wheezing disorder is common in preschoolers and disease control assessment is challenging as parents frequently overestimate the extent to which their child's disease is controlled. This is the first study of forced expiratory volume in t s (FEVt)/forced vital capacity (FVC) ratio measurements (i.e. FEV1/FVC, FEV0.75/FVC and FEV0.5/FVC) in wheezy preschoolers in relation to disease control. Our objective was to evaluate whether FEVt/FVC ratios less than the lower limit of normal (LLN; z-score <-1.64) were associated with uncontrolled wheezing disorder in preschoolers.Valid FVC, FEV1, FEV0.75 and FEV0.5 values were obtained in 92 healthy and 125 wheezy (62% uncontrolled) children (3-5 years). Associations between spirometry value